The nature and biological role of cellular cytotoxicity phenomena in alloimmune models is under study, with regard to the nature of effector cells (T cells, B cells, macrophages) and control mechanisms involved in the lytic process produced upon Cr51-labelled nucleated target cells. We propose to further develop methods for identification of surface markers on cell subpopulations and means for their separation in order to determine the characteristics of cells producing direct (sensitized) cytotoxicity and antibody-dependent cytotoxicity. The relevance of such assays, usually performed on peripheral blood or lymphoid tissue, to organ allograft rejection is under direct assessment by extracting infiltrating cells from rejecting rat and human tissue for direct study. The bidirectional control of cellular effector mechanisms by intracellular levels of the cyclic nucleotides, cAMP and cGMP, is exerted via a number of membrane receptors related to adenylate and guanylate cyclase activation. Current interest is in augmentation of cytotoxicity via cGMP elevations produced by acetylcholine or insulin, while the prostaglandins and methyl xanthines are effective in raising cAMP levels with reduction in cytolysis. Experiments are planned in an allograft model to assess the effects of several cyclic nucleotide active agents in vivo. Finally, cyclic nucleotide modulation of cell proliferation will be studied in a mixed lymphocyte culture system.